The Effect of chr16p11.2 Microdeletions and Microduplications on Gene Expression in Autism Spectrum Disorders and Schizophrenia.

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Abstract

The number of rare variants found to be associated with multiple psychiatric disorders is growing. One such locus is a recurrent ~600kb copy number variant (CNV) at 16p11.2, occurring in approximately 1% of autism and 0.3% of schizophrenia cases, as compared to 0.01% of the general population. (Sebat 2007, Kumar 2007, Weiss 2008, McCarthy 2009). This mutation has been found at a higher frequency in autistics and schizophrenics, but is also found in patients with developmental delay without an autistic diagnosis, and is also rarely seen in healthy individuals. Head circumference is observed to be smaller in deletion cases versus duplication cases. (McCarthy 2009) We hypothesize that one or more of the 25 genes at this locus contribute to the neurodevelopmental phenotype observed in patients with psychiatric disorders. To determine how gene function is altered by this CNV, we analyzed genome wide expression data from Epstein Barr Virus (EBV) transformed Lymphoblast cell lines (LCL), of patients with autism or schizophrenia who have deletions of reciprocal duplications of 16p11.2. Using RNA expression profiling by Affymetrix Human Genome U133 Plus 2.0 chip, we examined differential dosage and trans gene expression in individuals with 1, 2, or 3 copies of the genomic region. (6, 19, 16 respectively) To avoid skewing of data due to limited sample size we customized the Significance Analysis of Microarrays (SAM) method to utilize all samples while accounting for sources of bias. Our data highlighted 7 genes located both within and outside of the mutation which expression correlates with genotype. Some of these genes play a role in development while others have been associated with psychiatric disorders. We have analyzed our list of 7 dysregulated genes to identify pathways and functions relevant to neurodevelopment, and psychiatric disorders. Data generated by this study will give insight into dosage sensitive genes within the risk variant, and may help pinpoint genes which are relevant to pathology of the psychiatric disorders associated with this region.